The goals of the project are to acquire a better understanding of the immunopathogenic mechanism of noninfectious intraocular inflammatory diseases (uveitis) and to develop treatment and prevent the complications associated with these diseases. This past year we studied two specific aspects of the application of the new noncytotoxic immunosuppressant rapamycin (RAPA) in the treatment of uveoretinitis: (1) evaluation of the synergistic effect of RAPA with cyclosporine A (CsA) or dexamethasone (Dex) and (2) evaluation of the effect of RAPA on complications of uveitis, fibrosis, and intraocular membrane formation. We also evaluated the role played by nitric oxide (NO) in anterior uveitis. We demonstrated that combining RAPA with CsA or Dex can inhibit experimental uveitis in vivo at greatly reduced doses of each drug, compared with the doses necessary when these three drugs are used singly. We showed that RAPA also inhibits proliferation of human fibroblast and retinal pigment epithelial (RPE) cells, indicating the advantage of using RAPA in the treatment of uveitis, in which fibrosis and membrane formation are common complications. We also demonstrated that NO is an important mediator of endotoxin-induced anterior uveitis.